21-34887039-A-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_001754.5(RUNX1):c.155T>A(p.Met52Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000566 in 1,601,414 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M52I) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00060 ( 1 hom. )
Consequence
RUNX1
NM_001754.5 missense
NM_001754.5 missense
Scores
7
11
1
Clinical Significance
Conservation
PhyloP100: 6.86
Genes affected
RUNX1 (HGNC:10471): (RUNX family transcription factor 1) Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM1
?
In a domain Runt (size 128) in uniprot entity RUNX1_HUMAN there are 23 pathogenic changes around while only 6 benign (79%) in NM_001754.5
BS2
?
High AC in GnomAd at 41 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RUNX1 | NM_001754.5 | c.155T>A | p.Met52Lys | missense_variant | 4/9 | ENST00000675419.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RUNX1 | ENST00000675419.1 | c.155T>A | p.Met52Lys | missense_variant | 4/9 | NM_001754.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000270 AC: 41AN: 152132Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000258 AC: 60AN: 232566Hom.: 0 AF XY: 0.000249 AC XY: 32AN XY: 128548
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GnomAD4 exome AF: 0.000597 AC: 865AN: 1449282Hom.: 1 Cov.: 35 AF XY: 0.000560 AC XY: 404AN XY: 721512
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7Benign:1Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Uncertain:1Benign:1Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Likely benign and reported on 06-10-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Myeloid Malignancy Variant Curation Expert Panel | Jul 26, 2019 | The NM_001754.4:c.155T>A (p.Met52Lys) variant has a MAF of 0.00071 (0.071%, 6/8,456 alleles) in the EA Allele subpopulation of the ESP cohort that is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score >0.75 (0.845) (PP3). In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, PP3. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2023 | Observed in the germline of individuals with acute myeloid leukemia and acute lymphocytic leukemia in published literature (Yannakou et al., 2017; Drazer et al., 2018; Li et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23753029, 29365323, 28801348, 34166225) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RUNX1 p.M52K variant was identified in the literature in two individuals with acute myeloid leukemia (Mendler_2013_PMID:23753029; Drazer_2018_PMID:29365323). The variant was identified in dbSNP (ID: rs200431130) and ClinVar (classified as uncertain significance by the ClinGen Myeloid Malignancy Variant Curation Expert Panel, Invitae, and three other laboratories). The variant was identified in control databases in 65 of 263936 chromosomes at a frequency of 0.0002463, and was observed at the highest frequency in the European (non-Finnish) population in 61 of 122518 chromosomes (freq: 0.0004979) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.M52 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 10, 2017 | - - |
RUNX1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 13, 2023 | The RUNX1 c.155T>A variant is predicted to result in the amino acid substitution p.Met52Lys. This variant was reported as a germline variant in individuals with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (Mendler et al. 2013. PubMed ID: 23753029; Drazer et al. 2018. PubMed ID: 29365323; Li et al. 2021. PubMed ID: 34166225). One patient with AML also harbored variants in NPM1 and DNMT3A; therefore, it is unclear whether the RUNX1 variant was the primary cause of disease (Mendler et al. 2013. PubMed ID: 23753029). This variant is reported in 0.050% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-36259336-A-T). It is interpreted as a variant of uncertain significance by the ClinGen Myeloid Malignancy Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/239044/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 01, 2021 | - - |
Anaplastic ependymoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 29, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.;M;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;T
Sift4G
Uncertain
D;D;D;T;T;.;D
Polyphen
D;D;D;.;D;.;.
Vest4
MVP
MPC
2.0
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at